We propose a Resource for Native Mass Spectrometry Guided Structural Biology. The Resource will build, validate, and disseminate integrated workflows for structural characterization of protein:protein, membrane protein:lipid, and protein:RNA complexes that are critical for an array of cellular and organismal processes. The broad mission of the Resource is to empower biomedical researchers to use native MS workflows to define m/z, stoichiometry, heterogeneity, connectivity, topology, conformational diversity, and relative subunit binding strengths of protein complexes with high sensitivity and throughput. This information will guide selective integration of higher resolution structural biology tools. The overall goal of the Community Engagement Core of the Resource is to ensure the broadest possible access to optimized native MS instrumentation and workflows by fostering the active engagement of the national research community. We will do this by sharing workflows and technology in addition to fostering commercialization of the technologies developed in the Resource. In order to achieve this the resource will enlist and actively support Collaboration and Service projects that will benefit from the expertise and mature technologies available in the Resource at any given time. We have already identified 22 such projects, and as these projects develop we will actively seek new collaboration and service projects, working with the biomedical research community to make existing and emerging native MS technologies readily accessible and broadly available. In addition, the resource will improve understanding of native MS guided structural biology within the research community by training biomedical researchers to apply these novel methods to their own research questions. We will take a number of approaches in order to achieve this goal, including regular meetings with the Collaborate & Service and Driving Biomedical Projects teams, an annual short course at the American Society of Mass Spectrometry conference, an annual short course at the Resource, as well as hands-on training activities, and informative documents and videos on data analysis. The Resource will promote technology dissemination and commercialization of the developed resources to put cutting-edge native MS guided structural biology technologies and methods into the hands of biomedical researchers. In order to ensure rapid, sustainable dissemination, of the developed technologies, we will draw upon on our industrial and third party vendor collaborations to provide early adopters with pre-commercial products for use in their labs. We will start with a small number of beta testers and progress towards full commercial product offerings by multiple major instrument manufacturers, proposing instruments with different performance characteristics and different price ranges. Alongside the dissemination approaches detailed above, we will pursue traditional approaches, including publishing in peer reviewed journals and presenting the work at conferences, meetings, and symposia.